The DIO-1 (death inducer-obliterator-1) gene, identified by differential display PCR in pre-B WOL-1 cells undergoing apoptosis, encodes a putative transcription factor whose protein has two Zn finger motifs, nuclear localization signals, and transcriptional activation domains, expressed in the limb interdigitating webs during development. When overexpressed, DIO-1 translocates to the nucleus and activates apoptosis in vitro. Nuclear translocation as well as induction of apoptosis are lost after deletion of the nuclear localization sequences. DIO-1 apoptotic induction is prevented by caspase inhibitors and Bcl-2 overexpression. The in vivo role of DIO-1 was studied by misexpressing DIO-1 during chicken limb development. The most frequently observed phenotype was an arrest in limb outgrowth, an effect that correlates with the inhibition of mesodermal and ectodermal genes involved in this process. Our data demonstrate the ability of DIO-1 to trigger apoptotic processes in vitro and suggest a role for this gene in cell death during development.

Death inducer-obliterator 1 (DIO-1) is a gene that is upregulated early in apoptosis. Here we report that in healthy cells, the DIO-1 gene product was located in the cytoplasm, where it formed oligomers. After interleukin-3 starvation or c-Myc-induced apoptosis in serum-free conditions, DIO-1 translocated to the nucleus, where it upregulated caspase levels and activity. A nuclear localization signal deletion mutant (DIO-1⌬NLS) was unable to translocate to the nuclear compartment in the absence of interleukin-3 and failed to upregulate procaspase levels or trigger cell death. In addition, cells stably expressing DIO-1⌬NLS were protected from apoptosis induced by interleukin-3 withdrawal. These results indicate that DIO-1 has a relevant role in regulating the early stages of cell death.

No abstract

TABLE OF CONTENTS 1. Abstract 2. Introduction 3. NF-κB controls IL-2 gene expression 4. NF-κB and the IL-2 receptor 5. NF-κB and apoptosis 6. A dual role for NF-κB gene family members in programmed cell death 7. Role of NF-κB in IL-2-triggered T cell responses 8. Concluding remarks 9. References ABSTRACTThe NF-κB/Rel/IκB family of transcription factors regulates a number of genes involved in a wide variety of biological processes. The activation of p53, c-myc and Ras genes suggests a role for NF-κB in cell proliferation; NF-κB is also important in immune and inflammatory responses. By virtue of its role in apoptosis, NF-κB participates in the thymus as well as in embryonic development. The NF-κB family of transcription factors is also involved in viral transcription, transformation and in the development of some types of human cancers. Given the pivotal role of NF-κB, clarification is needed of the mechanisms through which its deregulation contributes to disease. Several aspects of NF-κB regulation, such as phosphatase involvement, the mechanism of IκB ubiquitination and the regulation of nuclear translocation, remain obscure. Here, we review and discuss the function of NF-κB activation in IL-2-stimulation and in apoptosis induced by IL-2 deprivation in T cells.